Does Route of Administration Affect the Outcome of Retinal Gene Therapy Clinical Trials?

Abstract

Luxturna^&#xae; (voretigene neparvovec-rzyl) for <i>RPE65</i>-associated retinal dystrophy was the first FDA-approved <i>in&#xa0;vivo</i> gene therapy and, 9 years later, remains the only approved retinal gene therapy. A search of clinicaltrials.gov identified 80 interventional phase 1-3 U.S. studies using AAV vectors, 45 using subretinal injection (SRI), and 33 using intravitreal injection (IVT). SRI efficiently transduces photoreceptors and RPE but transduces only the detached retinal area and carries procedure-related risks. IVT provides broader exposure and avoids retinal detachment but has shown limited efficacy for retinal targets and may produce dose-dependent inflammation. Overall, 11.6% of eyes in peer-reviewed publications receiving gene therapy via SRI experienced serious adverse events (SAEs); and in some studies, 100% experienced treatment-related adverse events (TRAEs). The gap between an active clinical pipeline and regulatory success raises the question: how does route of administration interact with therapeutic biology and clinical trial design? X-linked retinitis pigmentosa (XLRP) due to <i>RPGR</i> variants illustrates this challenge. Nine of 10 trials treating <i>RPGR</i>-related XLRP used SRI, with microperimetry and low light visual acuity as efficacy endpoints; 2 completed phase 2/3 studies failed to meet their primary endpoints. The XOLARIS XLRP natural history study suggests that other measures (e.g., visual field loss, central ellipsoid zone width) may better capture progression. Thus, retinal gene therapy clinical trial design must match the route of administration to the cellular target, therapeutic mechanism, and disease distribution. Emerging vectors and delivery strategies that expand retinal coverage while reducing procedural injury are critical to improve the likelihood of successful retinal gene therapy trials.